The project's broad goal is to define the roles of ocular blood flow in intraocular pressure (IOP) homeostasis and incorporate that information into a mathematical model of ocular hydrodynamics. The project's goal for this cycle is to increase our knowledge of episcleral venous pressure (EVP) and its regulation. This is important for two reasons. First, EVP is the pressure that aqueous must overcome to leave the eye via the trabecular outflow pathway, which makes it a principle factor in aqueous dynamics and IOP homeostasis. However, EVP is difficult to measure, so we know little about it and generally assume it is relatively stable. Given that the episcleral circulation is innervated and that most published EVP measurements were made under local anesthesia, that assumption is probably wrong. Rather, preliminary data obtained with a new technique show EVP is dynamic and regulated, and that fact will change our understanding of aqueous dynamics. Second, EVP is a heretofore unexplored target for lowering IOP in glaucoma patients, even though it has the potential to lower IOP significantly without the need for intraocular drug penetration. The next cycle has three specific aims: 1) translate our established rabbit model to a rat model for studying EVP (the rat outflow system is more similar to humans), 2) determine baseline values for relevant systemic and ocular parameters in the rat model, and 3) determine the neurotransmitters and receptors controlling EVP. The proposed research will increase our knowledge of the episcleral circulation and its role in aqueous dynamics, and reveal its potential as a new therapeutic approach for lowering IOP in glaucoma patients. PUBLIC HEALTH RELEVANCE: The project's goal is to increase our knowledge of episcleral venous pressure (EVP) and how it sets intraocular pressure (IOP), the primary risk factor and treatment target for glaucoma. EVP is difficult to measure, so we know little about it and generally assume it is constant; however, results obtained with a new technique show EVP is dynamic and regulated, and that lowering EVP lowers IOP significantly without the need for intraocular drug penetration. EVP is not now a target for glaucoma drugs, but it should be.